A CD19-OR-CD20 chimeric antigen receptor (CAR) protein construct is provided. Also provided are nucleic acids encoding the CD19-OR-CD20 CAR; and methods of use, e.g. in the treatment of B cell malignancies. The CD19-OR-CD20 CAR of the invention is a bispecific CAR that can trigger T-cell activation upon detection of either CD19 or CD20 (or both). It is a single molecule that confers two-input recognition capability upon human T cells engineered to stably express this CAR.

Provided is a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising one or more of the antigen binding motifs disclosed herein. Aspects of the disclosure relate to a polynucleotide encoding a chimeric antigen receptor (CAR) or a T cell receptor (TCR) comprising one or more of the antigen binding motifs. Provided are antibodies and antigen binding systems that comprise a binding motif that binds CD20 and optionally a binding motif that binds CD19, and methods of producing and using the same. Antibodies and antigen binding systems of the present disclosure comprise CARs that comprise an anti-CD20 binding motif and an anti-CD19 binding motif. Provided are compositions, such as antibodies and CARs that are or comprise an anti-CD20/anti-CD19 antigen binding system of the present disclosure, and cell therapies comprising the same, are useful, e.g., in the treatment of cancer.

Described herein are antigen binding proteins with specificity to Melanoma-Associated Antigen A4 (MAGE-A4) peptide-MHC (pMHC). Also described are multispecific antigen binding proteins comprising an antigen binding domain with specificity to CD3, and at least one MAGE-A4 pMHC antigen binding domain. Methods of treating cancer with the same are also described.

D domain (DD) containing polypeptides (DDpp) that specifically bind targets of interest (e.g., BCMA, CD123, CS1, HER2, AFP, and AFP p26) are provided, as are nucleic acids encoding the DDpp, vectors containing the nucleic acids and host cells containing the nucleic acids and vectors. DDpp such as DDpp fusion proteins, are also provided as are methods of making and using the DDpp. Such uses include, but are not limited to diagnostic and therapeutic applications.

Disclosed herein are methods of gene editing, or endogenous suppression, of cytokines/chemokines/transcription factors secreted from chimeric antigen receptor (CAR)-bearing immune effector cell such as CAR-T cells for the mitigation of cytokine release syndrome and/or CAR-T associated neuropathy. These methods involve insertion of the CAR into a locus of a cytokine gene, blocking its expression. Also disclosed herein are (CAR)-bearing immune effector cells with CARs inserted into a locus of a cytokine gene, and methods of treatment of diseases with immunotherapy with a reduced incidence of cytokine release syndrome and/or CAR-T associated neuropathy.

The present disclosure provides bispecific chimeric antigen receptors targeting CD20 and BCMA. The CAR may comprise an scFv targeting CD20 and an scFv targeting BCMA, a hinge region, a transmembrane domain, a co-stimulatory region, and a cytoplasmic signaling domain. The chimeric antigen receptors can be used to treat autoimmune disorders or cancer.

Adoptive T-cell therapy has shown tantalizing promise as a cancer treatment strategy, with several clinical trials reporting that T cells expressing chimeric antigen receptors (CARs) can eradicate tumors in patients with relapsed disease. However, CAR-T cells rely on receptor-mediated recognition of surface-bound antigens that are seldom tumor-exclusive, resulting in severe on-target, off-tumor toxicities that have led to patient deaths in clinical trials. There is a growing consensus that the lack of suitable antigens poses a major obstacle to the broad application of engineered tumor-targeting T cells. The ability to overcome T cells' reliance on surface antigen presentation and interrogate intracellular disease signatures would significantly expand the pool of detectable tumor markers and improve tumor-targeting specificity. Here, we present a novel strategy to reprogram T-cell-mediated cytotoxicity to interrogate intracellular disease signatures. We have engineered a switchable form of the cytotoxic protein Granzyme B (GrB) that is produced and delivered by T cells into target cells, but becomes active if and only if a tumor-associated protease is present inside the target cell. As a proof of concept, we have developed a GrB switch that responds to Sentrin-specific protease 1 (SENP1), an oncoprotein known to be overexpressed in prostate, pancreatic, and thyroid oncocytic tumor cells. We demonstrate that this GrB switch, termed cytoplasmic oncoprotein verification evaluator and response trigger (COVERT), is efficiently expressed and packaged by human T cells and properly trafficked to the immunological synapse between T cells and target cells. Furthermore, we show that COVERT is produced as an enzymatically inert protein that is activated by SENP1 in a dose-dependent manner. Finally, we describe designs to adapt COVERT into a modular platform technology that will expand the repertoire of candidate target antigens. We envision that COVERT can be utilized in combination with existing CAR technology to improve the tumor-targeting precision of cell-based immunotherapy.

Copyright American Institute of Chemical Engineers. All rights reserved.

The present disclosure provides modified cell(s), i.e., immune cell(s) or precursor cell(s) thereof, wherein the cell(s) are engineered to express: (a) a first chimeric antigen receptor (CAR) having affinity for CD19, and (b) a second CAR having affinity for a tumor antigen, wherein the tumor antigen is not CD19. Also provided are methods and uses of the modified cells, e.g., for treating at least one sign and/or symptom of cancer in a subject. The modified cells expand in the peripheral blood of the subject. Related nucleic acids, vectors, and pharmaceutical compositions are also provided.

The present invention provides compositions and methods for inducing a CAR mediated trans-signal in a T cell. The trans-signaling CAR T cells comprise a first CAR having a first signaling module and a second CAR having a distinct second signaling module. The present invention also provides cells comprising a plurality of types of CARs, wherein the plurality of types of CARs participate in trans-signaling to induce T cell activation.

The present invention relates to immune cells expressing chimeric antigen receptors against p95HER2 and bispecific antibodies for HER2 and CD3 and uses thereof in the treatment of cancer, in particular cancers which overexpress p95HER2.